Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethionine-induced hepatomas are characterized by high adenylate cyclase activity and cyclic adenosine 3',5'-monophosphate content relative to those of surrounding liver or liver from pair-fed control rats. The present study examined the properties of the guanylate cyclase-cyclic guanosine 3',5'-monophosphate (cGMP) system of these tissues. cGMP levels of the ethionine-induced hepatomas, determined in both specimens quick-forzen in situ and after in vitro incubation of tissue slices, were approximately 2 times higher than those of surrounding liver or controls. Higher cGMP in the tumors was associated with an increase in whole homogenate, soluble, and particulate guanylate cyclase activities, as well as an increase in soluble cGMP-phosphodiesterase activity. 3-Isobutyl-1-methylxanthine, a potent inhibitor of cGMP-phosphodiesterase activity, potentiated the differences in cGMP between slices of the hepatomas and surrounding liver or control, suggesting that the higher steady-state cGMP content of the tumors reflected enhanced basal cGMP synthesis which was partially offset by increased nucleotide degradation. In the hepatomas, a greater proportion of the total guanylate cyclase activity was located in the particulate cell fraction (31%) as compared to the subcellular distribution of enzyme activity in either surrounding liver or controls (15% of total in the particulate fraction). Carbamylcholine, which increased cGMP 3-fold in surrounding liver and controls, failed to alter cGMP levels inslices of hepatoma. Further, the relative changes in both cGMP accumulation and guanylate cyclase activity of the tumors in response to NaN3, NH2OH, and NaNO2 were blunted compared to surrounding liver or controls, although in each instance a response was clearly evident. Ethionine-induced hepatomas are thus characterized by: (a) significant increases in cGMP content and in guanylate cyclase and cGMP-phosphodiesterase activities, (b) a change in the subcellular distribution of guanylate cyclase, and (c) altered responsiveness of the guanylate cyclase-cGMP system to several agonists.
Cancer Res 1977 Jan
PMID:Increased guanylate cyclase activity and guanosine 3',5'-monophosphate content in ethionine-induced hepatomas. 1 87

Streptozotocin has been shown to induce the production of a variety of tumors in rats. The present report demonstrates that streptozotocin and 1-methyl-1-nitrosourea, a component of the streptozotocin molecule and a known carcinogen, stimulate the enzyme guanylate cyclase which catalyzes the production of guanosine 3',5'-monophosphate. At a maximal concentration of 3 mg/ml, these agents activated guanylate cyclase approximately 30-fold in liver, 20-fold in kidney, 15-fold in cerebellum. 15- to 30-fold in cerebrum, 4- to 20-fold inheart, 12-fold in brain stem, 10-fold in lung, and 2-fold in pancreas. Since recent evidence suggests a role for guanosine 3',5'-monophosphate in malignant transformation, the data may help explain the tumor-inducing capacity of these agents.
Cancer Res 1977 Jan
PMID:Activation of guanylate cyclase by streptozotocin and 1-methyl-1-nitrosourea. 1 88

The effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on the guanylate cyclase (GC)-guanosine 3'5' monophosphate (cGMP) system of rat colonic mucosa were studied. MNNG (1 mM) increased colonic mucosal cGMP from 1.8 +/- 0.2 to 22.5 +/- 2.7 pmol/mg protein in 5 minutes. Increases in response to MNNG occurred in the presence or absence of extracellular Ca2+, whereas the two-fold increase in mucosal cGMP mediated by carbamylcholine was abolished by exclusion of Ca2+. Although GC activity of mucosal homogenates was found predominantly (90%) in the 100,000 g particulate fraction, the effects of MNNG on mucosal cGMP correlated with stimulation of 100,000 g soluble GC by this agonist. MNNG increased soluble GC 13-fold over the corresponding basal with 4 mM Mn2+, and 48-fold with 4 mM Mg2+ as the sole available divalent cation. Compared with unstimulated GC, the MNNG-activated soluble enzyme was less dependent upon Mn2+ availability and effectively utilized Mg2+ as metal co-factor. N-ethylmaleimide, a sulfhydryl group alkylator, inhibited MNNG stimulation of GC and cGMP. Thus, expression of these MNNG actions may involve drug interaction with tissue thiol groups. Prior incubation of MNNG with thiol antioxidants or ascorbate also suppressed MNNG stimulation of GC, possibly through direct drug reactions involving nucleophilic and electrophilic reactants. The ability of MNNG to stimulate the colonic mucosal GC-cGMP system could be linked to its carcinogenic action.
Cancer 1977 Nov
PMID:Activation of the guanylate cyclase-guanosine 3'5' monophosphate system of colonic mucosa by n-methyl-n'-nitro-n-nitrosoguanidine. 2 43

Adenylate cyclase activity as well as intracellular content of sAMP were decreased 2.5-4-fold, as compared with normal state, in plasmatic membranes (PM) of hepatoma 22 and of Ehrlich ascites carcinoma--the tumors characterized by high level- of malignancy. Activity of cAMP phosphodiesterase exceeded distinctly the normal value in all the tumors studied. In less malignant hepatoma 48 the adenylate cyclase activity and content of cAMP were similar to those found in normal liver cells. The guanylate cyclase activity did not differ markedly from values found in normal liver cells in PM of all the tumors studied and in liver tissue of the tumor-bearing animals. Distinct alterations were not found in content of cGMP in the tumors, except of hepatomas 60 and 22, in which the nucleotide level exceeded 2-fold the normal value. The ratio cAMP/cGMP was decreased in the most malignant tumors. At the same time, the ratio was distinctly elevated in tumors with the middle level of malignancy (hepatomas 60 and 61).
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PMID:[Concentration of cyclic nucleotides, activity of adenylate cyclase, 3',5'-AMP phosphodiesterase and guanylate cyclase in plasma membranes from liver and hepatomas of different degrees of malignancy]. 3 Feb 12

4-Nitroquinoline 1-oxide (4NQO), a compound that induces tumors in various rat organs, rapidly increased the cellular accumulation of cyclic guanosine 3',5'-monophosphate (cGMP) to peak values fourfold to 13-fold over basal levels in the liver, lung, renal cortex, and gastric and colon mucosa of rats. This action of 4NQO was expressed in the presence or absence of extracellular calcium. When added directly to the broken cell preparations, 4NQO also stimulated guanylate cyclase activity threefold to sixfold over basal levels in the 100,000 X g soluble fractions of each of these tissues. Dicumarol, which blocks the reduction of 4NQO, inhibited 4NQO stimulation of guanylate cyclase and cGMP. Conversely, phenythydrazine, which enhances the reduction of 4NQO, potentiated the actions of 4NQO on guanylate cyclase and cGMP. These results suggested that the activation of the guanylate cyclase-cGMP system may be mediated by reduction products of 4NQO. The activation of the guanylate cyclase system by 4NQO or its derivatives could function in the expression of carcinogenicity.
J Natl Cancer Inst 1977 Dec
PMID:Stimulation of soluble guanylate cyclase activity and cellular accumulation of cyclic guanosine 3',5'-monophosphate by the carcinogen 4-nitroquinoline 1-oxide: brief communication. 7 27

This paper review the actual knowledges about the physiological role of nitric oxide, sintetized from amino acid L-arginine. The nitric oxide sintetized in the vascular endothelium has a fundamental role in vascular tone, blood flow and arterial pressure control, acting stimulating guanylate cyclase on vascular smooth muscle. Nitric oxide could be considered the endogenous nitrovasodilator. Its action on the cardiovascular system are imitated by nitroglycerine, sodium nitroprusside and related compounds. Probably the disturbance in the synthesis or release of nitric oxide may be involved in the pathophysiology of hypertension, vasospasm and atherosclerosis. Recently has been shown that nitric oxide synthesis from L-arginine also occurs in other different cells like macrophages, central nervous system, liver, neutrophils, adrenal glands, playing different biological effects. Changes in nitric oxide synthesis or action in those systems, could be related to different pathological disorders as inflammation, atherosclerosis and cancer. The found of a substance as simple as nitric oxide, let suppose that we are in the presence of a biological mediator with a very early evolutionary origin, probably widespread in all the animal kingdom, and which represents the universal transduction system for activation of the soluble guanylate cyclase enzyme.
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PMID:[Nitric oxide: from endogenous vasodilator to biologic mediator]. 209 54

To directly compare clinical side effects and biological response modification, IFN-beta ser, IFN-gamma, or the combination of IFN-beta ser plus IFN-gamma was administered to 21 cancer patients. Each IFN or the combination was given intravenously on days 1, 8, and 15 in varied order. Each IFN and the combination resulted in significant (P less than 0.05) modulation of IFN-induced proteins. IFN-beta ser was more effective than IFN-gamma in enhancing 2-5A synthetase activity (P = 0.001). IFN-gamma was more effective than IFN-beta ser in enhancing serum beta 2 microglobulin expression (P = 0.05) and indoleamine dioxygenase activity, as assessed by decreased serum tryptophan (P = 0.03). The combination enhanced tryptophan catabolism more effectively than IFN-beta ser in a dose-dependent manner (P less than 0.03). IFN-beta ser/IFN-gamma did not potentiate natural killer cells or antibody-dependent cellular toxicity (ADCC). IFN-beta ser/IFN-gamma enhanced monocyte guanylate cyclase activity, as assessed by serum neopterin, more effectively than IFN-gamma alone (P = 0.005). Both IFNs and the combination resulted in increases in HLA class II expression on monocytes. However, no significant difference in the level of induction of HLA DQ and HLA DR expression between IFN-beta ser/IFN-gamma and either IFN-beta ser or IFN-gamma was noted. Although frequency and servity of side effects of IFN-beta ser, IFN-gamma, or the combination were dose related, induction of induced proteins (with exception of influences on tryptophan catabolism) were not a function of dose administered over the 10-fold range. Continued treatment with the combination intravenously three times a week for 4 wk sustained but did not further potentiate, most of the changes in interferon-induced proteins. Thus, IFN-beta ser and IFN-gamma each resulted in effective and essentially equivalent patterns of induction of induced proteins. When combined, however, these IFNs did not result in potentiation of biological response modification in vivo.
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PMID:A direct comparison of biological response modulation and clinical side effects by interferon-beta ser, interferon-gamma, or the combination of interferons beta ser and gamma in humans. 212 Feb 84

The author reviews the problem of the pattern of lipid peroxidation in cancer cells with special reference to a comparison between normal liver cells and hepatomas both transplanted and induced by diethylnitrosamine. It is stated that the loss of lipid peroxidation is proportional to the degree of de-differentiation of hepatoma cells. During carcinogenesis, however, the loss is already evident at the stage of preneoplastic nodules. A common feature of all tumors, independently of the extent of the loss of peroxidation in basal conditions, is the lack of further stimulation by ADP/iron or by ascorbate/iron. As regards the reasons for the decline in lipid peroxidation, they are certainly not unique. An important cause is the low activity of the enzymes of the monooxygenase microsomal chain. Another very important one is the change in lipid composition of membranes, with a marked decrease in polyunsaturated fatty acids, which are the main substrate for lipid peroxidation. It has been shown that enrichment of membranes of hepatomas with arachidonic acid results in restoration of stimulation of peroxidation by ascorbate/iron, but not with ADP/iron. The last type of stimulation mostly reflects the behaviour of the monooxygenase chain, whereas ascorbate/iron-induced stimulation does not require the presence of an efficient cytochrome P450-chain. Another cause for decreased lipid peroxidation in tumors is the increased rigidity of membranes, due to the large increase in cholesterol content: this prevents to some extent the influx of oxygen inside the membranes. Yet another cause is the presence of increased amounts of antioxidants in both cytosol and membranes. The main toxic product of lipid peroxidation, 4-hydroxynonenal, has been found to elicit several actions at extremely low concentrations. In fact, 4-hydroxynonenal stimulates chemotaxis of polymorphonuclear leukocytes, stimulates plasma membrane adenylate cyclase, stimulates plasma membrane guanylate cyclase, and stimulates phospholipase C. The last three enzymes involve the action of G-proteins. The effect of the aldehyde is present at less than micromolar concentrations, which may occur inside the cells in certain conditions. Moreover, at concentrations from 10(-6) to 10(-7) M, the aldehyde is able to block oncogene c-myc expression in the human erythroleukemic K562 cell line, which at the same time becomes able to express the gamma-globin gene. These facts are discussed with reference to a possible biological meaning of the loss of lipid peroxidation in tumors.
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PMID:Lipid peroxidation and cancer: a critical reconsideration. 251 Mar 83

Because recent observations indicate that metabolism of cyclic nucleotides may be altered in neoplastic cells, the intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) were measured in mononuclear leukaemic and normal human leucocytes. The activities of adenylate cyclase, guanylate cyclase and cyclic nucleotide phosphodiesterases were also determined. Under basal conditions, cAMP levels were always higher in the normal leucocytes, whilst cGMP levels were of the same order of magnitude in both normal and leukaemic cells, causing the cAMP/cGMP ratios to be significantly lower in leukaemic leucocytes. Leukaemic cells significantly increased cyclic nucleotide levels in response to theophylline, but did not respond to serotonin, carbamylcholine or D,L-isoproterenol. Preincubation of these leucocytes with theophylline produced a detectable cAMP response to D,L-isoproterenol but no cGMP response to serotonin or carbamylcholine was found. Adenylate cyclase and guanylate cyclase were significantly lower in leukaemic than in normal cells, which could largely explain the abnormal cyclic nucleotide pattern found in human leukaemic leucocytes. In our experiments, cAMP phosphodiesterase activity was comparable in normal and leukaemic cells, whereas cGMP phosphodiesterase activity was undetectable inall mononuclear-leucocyte preparations with the methods used.
Br J Cancer 1980 Mar
PMID:Patterns of cyclic nucleotides in normal and leukaemic human leucocytes. 610 1

The anthracycline antibiotic doxorubicin induces a variety of cardiotoxic effects. We have recently demonstrated that this drug also causes a selective inhibition of rat and human cardiac guanylate cyclase activity in vitro. In the present study, we examined the effect of 30 analogs of doxorubicin on cardiac guanylate cyclase activity. Structural modifications of these anthracycline antibiotics were found to alter their effect on rat cardiac guanylate cyclase activity, N-Substitutions on the sugar moiety eliminated the inhibitory action observed with the parent compound. Long-chain hydrocarbon substitutions in place of the methylketone side chain had a similar effect. Removal or substitution of the C-4 methoxy group had little or no effect on the ability of these compounds to modify guanylate cyclase activity. Substitutions of the C-9 side chain by a hydrazone derivative resulted in compounds that stimulated the enzyme. All of the anthracenedione derivatives were inhibitory. A comparison of the inhibitory effect of some of these anthracycline derivatives on in vitro cardiac guanylate cyclase activity with their cardiotoxic potency suggests a possible relationship between these two parameters.
Cancer Treat Rep 1982 Feb
PMID:Inhibition of cardiac guanylate cyclase by doxorubicin and some of its analogs: possible relationship to cardiotoxicity. 612 40


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